HIV Mediated Dysfunction of Neural Progenitor Cells

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): The introduction of highly active antiretroviral therapy (HAART) regimes in the mid-1990's has resulted in a 40-50% decrease in the incidence of HIV-associated dementia (HIVD). Nonetheless, AIDS-associated neurological diseases continue to be major causes of morbidity and mortality, and in some cohorts, the prevalence of HIVD is on the increase, despite effective peripheral control of viral replication. We hypothesize that a dysfunction of neural progenitor cells in the hippocampus contributes to the neurological manifestations of HIVD. The formation of new neurons (neurogenesis) occurs through adult life and is thought to contribute to the processes of learning and memory. Neurodegenerative and neuroinflammatory conditions interfere with neurogenesis and thus disrupt memory formation by preventing the functional incorporation of new neurons into existing hippocampal circuitry. HIV and HIV-derived proteins are known to promote neuroinflammation and can induce the dysfunction and death of neural cells though direct actions at chemokine receptors and by indirect effects that are mediated by macrophages and glia. It is thus possible that HIV and HIV proteins contribute to learning and memory deficits in HIV-infected patients by disrupting neural progenitor cell function. In preliminary experiments we have characterized the expression of chemokine receptors in two populations of neural progenitor cells and have evidence that the HIV-1 protein Tat disrupts neurogenesis in vitro and decreases the proliferation rate of neural progenitor cells in the molecular layer of the dentate gyrus of mice transgenic for Tat. Using a multilineage human neurosphere model and purified populations of lineage-restricted progenitor cells, we propose to determine the effects of HIV-1 and the HIV-1 proteins gp120 and Tat on neural progenitor cell proliferation, survival and cell fate decisions. Findings from our in vitro studies will be confirmed in mice transgenic for gp120 or Tat by quantification of differences in neural progenitor cell proliferation, survival and function. The object of these studies is to identify and characterize mechanisms of HIV, gp120 and Tat-mediated dysfunctions in neural progenitor cells. Findings from these studies could identify novel therapeutic targets for the treatment of HIV-related neurological disease.